Yersinia pestis is the etiologic agent of pneumonic plague. Antibiotic-resistant strains of Y. pestis exist, and no licensed vaccine can prevent pneumonic plague. As such, intentionally aerosolized Y. pestis has the potential to cause a devastating pandemic. Subunit vaccines comprised of the Y.pestis F1 and/or V proteins provide mice and non-human primates with significant, but incomplete, protection against aerosolized plague. Neutralizing antibodies apparently play an important role in that protective response. CD4+T cells presumably contribute to protection as well, since they are critically important for memory B cell responses and the affinity maturation of antibodies. We hypothesize that, in addition to stimulating, maintaining, and/or boosting antibody responses, appropriately primed CD4+T cells can also direct cellular immunity at host cells harboring Y. pestis organisms. Relevant prior studies have been limited in scope, although they established that the F1 and V proteins do elicit significant CD4+T cell responses. Here, we propose to (i) determine the immunodominant epitopes recognized by V-specific CD4+T cells in C57BL/6 mice, (ii) develop sensitive assays for quantifying cytokine-producing V-specific T cells, (iii) optimize vaccination protocols to recruit V-specific CD4+T cells to inflamed pulmonary tissues, and (iv) decisively evaluate the capacities of vaccine-primed CD4+T cells to protect against pneumonic plague. Through these studies we will specifically test our hypothesis that vaccine-primed CD4+T cells can combat pneumonic plague via their capacities to stimulate cellular immunity. Subsequent experiments will decipher the precise underlying mechanisms, and strive to develop vaccination protocols that optimally elicit those activities. Acquiring direct information about the activation, expansion and persistence of Y. pestis-specific CD4+T cells in lung and lymphoid tissues, and optimizing vaccination strategies to harness the protective capacities of those cells, will undoubtedly aid the development of effective pneumonic plague vaccines.